The present invention relates to new oral multi-unitary pharmaceutical preparations containing substituted benzimidazoles being inhibitors of H+, K+-ATPase (i.e. omeprazole, lansoprazole, pantoprazole, leminoprazole and pariprazole) or their pharmaceutically acceptable salts. The preparations comprise a spherical inert core, constituted by starch and sugar, coated with a layer containing at least one substituted benzimidazole in the micronized form, which is mixed with pharmaceutically acceptable inert excipients, whose proportions are suitable for allowing the disaggregation of the dosage forms and the intended dissolution of the active ingredient(s), this layer in turn being coated with an insulating layer of an exclusively polymeric nature and of suitable thickness, applying lastly an external, gastroresistant or enteric layer of suitable thickness, in order to guarantee the integrity of the product until it reaches the proximal part of the small intestine, where the formulation will be disaggregated to facilitate the absorption of the substituted benzimidazolic compounds. The pellets produced according to the invention are placed in hard gelatine capsules and administered to patients in this form. The invention does not require the stabilization of the benzimidazolic compounds using any of the strategies or processes which already belong to the state of the art. Besides, the pharmaceutical products produced in this way are free from organic solvents and/or the impurities generally associated to them, because the application of the different layers exclusively requires aqueous solvents. This aspect constitutes a technological advantage, since the manufacturing process is incomparably safer, because there is no toxicity risk to operators or explosion risks and moreover it is more ecological, because there is no possibility of environmental contamination caused by organic solvents leaking into the atmosphere. Finally, it is much safer for the patient, because there is no need to consider solvents and/or residual impurities associated to them, which is a considerable advantage in terms of public health. For the manufacture of the products, only equipment is requiredxe2x80x94a fluid bed equipment with an inner partition device (wurster). The products obtained by extrusion/spheronization, by rotogranulation or by xe2x80x9cpowder coatingxe2x80x9d are completely outside the scope of the present invention.
The products obtained are stable for a period of time compatible with pharmaceutical requirements, and they present gastroresistance and dissolution characteristics generally adapted to the period of validity established for pharmaceutical products (i.e. 3 years).
Benzimidazolic compounds such as omeprazole (5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-sulfinyl)1H-benzimidazole (EP-B1-0005129), lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroetoxy)-2-piridyl)methyl(sulfinyl 1H-benzimidazole) (U.S. Pat. No. 4,628,098), pantoprazole (U.S. Pat. No. 4,758,579)), leminoprazole and pariprazole are anti-ulcerous substances known for decreasing gastric acid secretion (Olbe L., et al., Gastroenterol., 83:193-198 (1982); Saton H. et al., Jpn. J. Pharmacol. 40 (suppl.), 226 (1986); Saton H, et al., J.Pharmacol. Exp. Ther, 248 (2), 806-815 (1989), Nagaya, H, et al., J.Pharmacol. Exp. Ther., 248 (2), 799-805 (1989)) and they are used in the therapeutics of diseases related to gastric acidity in mammals and especially in humans, including gastric and duodenal ulcers, reflux oesophagitis, gastritis, duodenitis and Zollinger-Ellison syndrome.
It is also known that these substituted benzimidazoles possess a very low level of solubility in water, they solubilize easily in alkaline solutions (i.e. the txc2xd of degradation of omeprazole in aqueous solutions of pH greater than 11 is 600 days), they degrade quickly in acidic and neutral media (i.e. the txc2xd of degradation of omeprazole in aqueous solutions of pH less than 4 is 10 minutes) (Pilbrand and Cederberg, Scand. J. Gastroenterol, 20 (Suppl. 108), p. 113-120 (1985)) and they are stabilized in the presence of alkaline reacting compounds. The maximum stability of omeprazole solutions is reached at pH 11; for pHs lower than 7.8, degradation occurs very quickly (Drug.Dev.Ind.Pharm., 21(8), 965 (1995). Lansoprazole is relatively stable when exposed to the light. This compound degrades in aqueous solution, its degradation speed increasing as the pH decreases. For this reason, whenever the oral route is used it is indispensable to coat the formulations with a gastroresistant layer, in order to avoid contact between the active ingredient and gastric content with acidic characteristics. On the other hand, it is necessary that the formulations dissolved quickly in the intestine, where the benzimidazolic compounds should be absorbed, i.e. when the pH becomes higher than 6.8. Several pharmaceutical preparations containing substituted benzimidazole inhibitors of H+,K+-ATPase are already patented.
The first assays performed with classic enteric pellets containing omeprazole showed that they did not present suitable stability during a long enough period of time to be used in a satisfactory pharmaceutical dosage form, because fast degradation of the active ingredient was observed when subjected to normal conditions of storage (T=25xc2x11xc2x0 C. and HR=40-75%), with the appearance of noxious degradation products (Brandstrom A., et al., Acta Chemica Scandinavia, 43, 536-548 (1989)).
DE-A1-3046 559 describes a way to coat a pharmaceutical dosage form with an insoluble layer containing microcrystalline cellulose and with a second enteric layer. This preparation did not allow the desirable release of omeprazole in the small intestine.
U.S. Pat. No. 2,540,979 describes a preparation coated with an enteric layer combined with a first coating of a water-insoluble wax. This preparation was shown to be inadequate for omeprazole because the direct contact of the cellulose acetophtalate (CAP) with the omeprazole caused its degradation.
DE-A1-1 204 363 describes a pharmaceutical dosage form which has three layers but cannot be used for omeprazole because it does not allow the fast release of omeprazole in the small intestine, as is desirable. DE-A1-1 204 363 concerns a coating that allows the delivery of the active ingredient in the ileum, which is not desirable in the case of omeprazole.
DE-A1-1 617 615 describes a dosage form which likewise cannot be applied to omeprazole because it is dissolved very slowly in the intestinal juice.
GB 2 189 698 A and U.S. Pat. No. 4,786,505 propose the mixture of a mass of cellulose derivatives and disaggregants, with an appropriate amount of omeprazole and alkaline salts, in order to obtain, by extrusion, a core which is spheronized and coated with gastroresistant agents dissolved in alcoholic solutions also containing considerable percentages of acetone. However, the pellets obtained are extremely irregular in shape and dimensions, which hinders the process of filling the gelatine capsules, and this can have repercussions on a relative dispersion of the average weight of the capsules and of the respective dosage. Besides, the use of organic solvents in any of the phases of preparation of the pharmaceutical dosage forms means that the quantity thereof in the final product will have to be determined, as well as the quantity of the impurities that may be associated to them and may be potentially dangerous for the health, which makes them highly inadvisable.
U.S. Pat. No. 5,232,706 describes omeprazole dosage forms coated with one or more layers containing water-soluble alkaline excipients mixed with a second alkaline compound.
U.S. Pat. No. 5,385,739 and FR-A-2 692 146 describe pharmaceutical gastroprotected dosage forms containing omeprazole wherein the active substance is diluted with mannitol and applied to an inert core. The dosage form is prepared in a conventional coating pan, which is a slow process and requires the use of organic solvents which are noxious to the operator and dangerous to handle. Besides, with the pellets obtained, with a wrinkled surface, it is difficult to fill capsules of uniform weight. Finally, the pellets marketed by the applicant of these patents did not observe the gastroresistance and dissolution criteria required for their use during the period of validity established for pharmaceutical dosage forms.
U.S. Pat. No. 5,399,700 concerns the stabilization of benzimidazolic derivative compounds as cyclodextrin inclusion complexes.
U.S. Pat. No. 5,690,960 concerns dosage forms containing magnesium omeprazole salts with more than 70% crystallization.
U.S. Pat. No. 5,708,017 concerns an oral formulation in the form of a paste in an oily vehicle, containing a proton pump inhibitor, intended for the treatment of gastric ulcers in humans and animals.
U.S. Pat. No. 5,714,504 relates to pharmaceutical formulations for oral administration containing alkaline salts of the (xe2x88x92) enantiomer of omeprazole.
WO 96/01623 relates to omeprazole tablets obtained from gastroresistant multi-unitary dosage forms, which are used to prepare tablets in the presence of appropriate excipients.
WO 97/12581 relates to oral formulations of omeprazole obtained by compression of pellets containing benzimidazoles, thereby obtaining micro-tablets which are subsequently coated and placed in hard gelatine capsules.
WO 98/53803 relates to the specific use of a quality of HPMC in the manufacture of pharmaceutical dosage forms containing omeprazole.
WO 98/19668 relates to an omeprazole formulation with pulsatile kinetics which simulates a bolus for a once-a-day dosage form.
WO 98/50019 relates to oral dosage forms containing omeprazole or lansoprazole, inside hard gelatine capsules which are subsequently coated with gastroresistant or enteric polymers.
U.S. Pat. No. 4,689,333 describes pharmaceutical compositions for the prevention or treatment of ulcers containing an effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.
U.S. Pat. No. 5,026,560 relates to spherical pellets consisting of a core coated with a binding agent which is coated with a mixture of powders containing lansoprazole, HPMC of low viscosity and magnesium or calcium carbonates as alkaline agents. The manufacturing process used was xe2x80x9cpowder coatingxe2x80x9d, which is difficult and laborious and therefore makes the product very expensive.
U.S. Pat. No. 5,045,321 relates to dosage forms for the production of pellets or coated tablets which comprise a uniform mixture of lansoprazole with at least one alkaline inorganic salt. There is no reference to protective and/or enteric coatings in the claims of the patent.
U.S. Pat. No. 5,093,132 claims a stable oral dosage form containing lansoprazole or a pharmaceutically acceptable salt thereof mixed uniformly with an alkaline inorganic salt as a stabilizing agent. Only a simple reference is made to the use of an enteric coating.
EP 0 589 981 relates to oral dosage forms of pantoprazole as tablets or pellets which use alkaline and/or alkaline-earthy metallic salts for stabilization of the active ingredient and which use organic solvents (i.e. isopropanol) in the technological process for the production of the pharmaceutical formulations.
WO 97/12580 describes oral dosage forms of substituted benzimidazoles, preferably pantoprazole, obtained by compression of pellets containing benzimidazole, thereby producing micro-tablets that are subsequently coated and placed inside hard gelatine capsules.
The present invention concerns stable multi-unitary dosage forms of gastroresistant pellets for oral administration, free from residues of organic solvents and the impurities associated to them, containing a substituted benzimidazole or a pharmacologically acceptable salt thereof, or associations of substituted benzimidazoles or of their pharmaceutically acceptable salts. The formulations do not comprise any of the methods of stabilization of benzimidazoles already known from the state of the art and they are the first ones whose manufacturing process involves the use of a fluid bed equipment with an inner partition device (wurster), and not extrusion/spheronization techniques, rotogranulation, xe2x80x9cpowder coatingxe2x80x9d or coating in conventional coating pans. Thus, the present invention describes pellet formulations composed of an inert core coated with a layer which contains the active ingredient(s), coated in turn with an intermediate layer of a minimum thickness of 15 xcexcm and with a final external gastroresistant or enteric layer of a minimum thickness of 30 xcexcm. The thickness of the intermediate layer is decisive to the stability of the final product and it prevents the incorporation of alkaline and/or alkaline-earthy metallic salts into the mixture containing the benzimidazolic compounds, as well as into the insulating layer. The pellets obtained have spherical symmetry and their surface is perfectly flat when observed by scanning electronic microscopy (S.E.M.), contrary to the other formulations on the market that are obtained by other methods. In addition, the fact that the products are manufactured without the use of organic solvents makes them safer for patients and for operators who manufacture and handle them. The manufacturing process does not cause environmental pollution problems, which are becoming increasingly essential to avoid, and this is another of the aspects that differentiate these formulations from those belonging to the state of the art. Moreover, the process for manufacturing these new formulations has technical as well as economic advantages. In fact, all the stages of the manufacturing process use the same equipment, which represents less contact for the operator with the product, contrary to what happens with the other described processes which require the transfer of the pellets from the extruder/spheronizer to the coating pans or fluid bed equipments in order to be coated. Neither does it involve various equipments of restricted use and a high cost, which would have to be reflected in the final price of the product to consumers. These facts, together with the high market prices of benzimidazolic compounds, lead to an exaggerated increase in the price of the final product, which will necessarily be borne by patients who need the medication. The present invention seeks to reduce the production costs of these products in order that they can be used on a large scale all over the world.
The present invention describes multi-unitary pharmaceutical dosage forms containing a substituted benzimidazole (omeprazole, lansoprazole or pantoprazole, leminoprazole or pariprazole) or a salt thereof, or associations of benzimidazoles or their salts, constituted by a succession of layers arranged around an inert, spherical core, prepared in a fluid bed equipment with an inner partition device (wurster). The component elements of the dosage form are:
(1) inert core,
(2) active layer,
(3) insulating layer and
(4) gastroresistant or enteric coating layer.
The inert cores of dimensions of 600-710 xcexcm, 710-850 xcexcm or 850-1000 xcexcm, constituted by pharmaceutically acceptable inert excipients are coated with a layer containing at least one benzimidazole or its salts, mixed with pharmaceutically acceptable inert excipients, so that this layer is quickly disaggregable. This layer is then coated with an insulating layer of a strictly polymeric nature, of a minimum thickness of 15 xcexcm, and finally this layer is coated with an enteric coating layer of a minimum thickness of 30 xcexcm. The pellets have spherical symmetry and a flat surface, are free from residues of organic solvents and the impurities associated to them and they have a moisture level that guarantees good stability under normal storage conditions. The pellets are placed in hard gelatine capsules and it is in this form that they are administered to patients. The formulations with this composition are characterized in that they do not dissolve in an acid medium, but dissolve quickly at an alkaline pH and present good stability in terms of dosage and in gastroresistance and dissolution assays, when stored for at least 3 years.